The objective of the proposed research is to develop a safe and effective vaccine for severe acute respiratory syndrome (SARS) using a single-cycle, alphavirus replicon vaccine vector that has been derived from an attenuated strain of Venezuelan equine encephalitis (VEE). Candidate VEE replicon vaccines expressing each of the major SARS-CoV (Urbani strain) structural proteins (S, M, N, and E) have been constructed and shown to be highly immunogenic in mice when inoculated alone or in combination. These candidate vaccines will be characterized in vitro and evaluated in vivo using a murine challenge model of SARS for immunogenicity, efficacy, safety and the possibility of immune enhancement. The specific aims are (1) to generate SARS-CoV-specific immune reagents (antigens and reagent antibodies) required for vaccine manufacture and to monitor immune responses in vaccinated animals, (2) to carry out safety, immunogenicity and protection studies in a murine challenge model to identify an optimal VRP vaccine for SARS, (3) to carry out process optimization studies to facilitate GMP-compliant manufacture, and (4) to manufacture a GMP compliant, multivalent, VRP vaccine for SARS suitable for clinical evaluation. SARS is a highly infectious emerging disease of humans. There are no antiviral drugs or vaccines effective against SARS and the world's population is assumed to have no immunity. Given the highly infectious nature of the virus, SARS must be considered to represent a global health emergency. A safe and effective vaccine that could be used to protect attending medical staff and eventually larger populations at risk would be a valuable adjunct to public health measures, and possibly the only realistic solution to widespread outbreaks. Based on the proposed studies, an optimal vaccine candidate will be selected, carded through production scale-up, preclinical studies, pilot lots, and GMP manufacture. GLP-compliant toxicology studies suitable to support an IND submission will be carried out on the manufactured product.